Immunoglobulin E (IgE) plays a central role in atopic hypersensitivity conditions including allergic rhinitis, allergic asthma, food allergies, and contact allergies (atopic dermatitis) and non-atopic hypersensitivity conditions including anaphylaxis, urticaria, and hives (Galli and Lantz, 1999, Fundamental Immunology, ed. Paul, p. 1127). IgE is identified as the presumptive causative agent responsible for passive transfer of cutaneous reactivity to allergens. Serum levels of IgE were shown to correlate closely with cutaneous reactivity to common allergens, as well as with bronchial hyper-responsiveness (Sears et al., 1991, N. Engl. J. Med., 325:1067). Syndromes of allergic rhinitis and asthma are attenuated when levels of circulating IgE are neutralized by antibodies (Chang, 2000, Nature Biotech, 18:157).
IgE-mediated allergic inflammation is believed to be initiated upon triggering of IgE-sensitized mast cells with allergens. Inflammatory mediators include antihistamine and leukotrienes. The most common therapeutic approach to allergic inflammation is to block target organs from inflammatory mediators secreted by mast cells, for example through the use of antihistamines, which are believed to block the binding of histamine to their H1 receptors on vascular endothelial cells and vascular, respiratory, and gastrointestinal smooth muscle cells. Antihistamines are particularly helpful in allergic rhinitis, ocular allergies, urticaria, and atopic dermatitis. Newly developed non-sedating antihistamines are popular. However, antihistamines have been minimally beneficial in allergic asthma, and have little ability to affect the expression of chronic allergic inflammation in the airways of these patients. Several different leukotriene receptor antagonists are now available, and these agents show promise in reducing the signs and symptoms of chronic allergic asthma. Although these agents are generally preferred to antihistamines in this clinical setting, they only partially attenuate clinical evidence of the disease (Boushey, 2001, J. Allergy Clin. Immunol., 108:S77) probably due to the multiple entities of mast cell small molecules mediators as well as a host of cytokines such as interleukin 4 (IL-4), interleukin 5 (IL-5), and tumor necrosis factor alpha (TNF-alpha), and eotaxin and other chemokines secreted by mast cells (Willis-Karp, 1999, Annu. Rev. Immunol., 17:255).
As an alternative to the complexity of blocking the pharmacological effects of mast cell mediators, there have been various approaches to competitively inhibit IgE binding to and sensitization of its type I high affinity Fc receptor (FceRI). FceRI receptor antagonists can be for example, a long piece of IgE polypeptide of 72 amino acids in length derived from constant region heavy chain domains of CH2 to CH3 (Helm et al., 1988, Nature, 331:180). Moreover, there have been reports that short synthetic peptides from five to sixteen amino acid sequences from the CH4 domain interfere with direct IgE sensitization to FceRI on mast cells (Stanworth et al., U.S. Pat. No. 5,955,076).
Immunotherapy by allergen desensitization aims to shift the immune system response from developing Th2-type helper T-lymphocytes to Th1 helper T-lymphocytes. The general paradigm is that interleukin-4, secreted by Th2, plays a central role in initiating and augmenting allergen-specific IgE production. Interleukin-4 in turn plays a key role in skewing dichotomous T-lymphocyte development into the Th2 subset, thus further augmenting IgE production. Th2 commitment, in turn is believed to lead to production of more IL-4 (Mosmann and Coffman, 1989, Ann Rev. Immunol., 7:145). A source of endogenous IL-4 is also believed to be contributed by mast cells and basophils, by a unique subset of IL-4 secreting CD8+T-lymphocytes, and by NK1.1+CD4 T-lymphocytes. There have been numerous attempts to downregulate Th2 development by administering recombinant allergens to patients, but due to the multiple sources of IL-4 and the complex cytokine feedback circuits in dichotomous CD4 T-lymphocyte development, this approach tends to yield variable results (Kay and Lessof, 1992, Clin. Exp. Allergy, S3:1; Seymour et al., 1998, J. Exp. Med., 187:721).
Another approach to down-regulate the levels of circulating IgE resides is the administering of an anti-IgE antibody, that is to say, passive immunization against IgE. One such anti-IgE antibody recognizes a mast cell IgE binding site and thus blocks IgE sensitization to mast cells (Chang, 2000, Nature Biotech., 18:157). The partially humanized monoclonal antibody E25 (MAb-E25) (Chang, U.S. Pat. No. 5,428,133) is currently in a Phase III clinical trial. Passive immunization against anti-IgE results in the scavenging of circulating IgE, but would not be expected to substantially inhibit IgE production in atopic patients. Additionally, it has been shown that circulating IgE-anti-IgE complexes accumulate to a level ten-fold higher in passively immunized patients than that prior to treatment. This result is probably due to the increase in half-life of circulating IgE from about 2 days (circulating free IgE) to about 14 days (IgE-anti-IgE complexes), possibly because the humanized IgG used as the passive vaccine protects IgE from degradation. One concern from this is that IgE dissociated from the IgE-anti-IgE complex may sensitize mast cells. Another disadvantage to this passive vaccine is that a high dose of 300-500 mg per patient is routine. Benefits of anti-IgE treatment appear transiently during the period of intensive treatment, and the patient's condition significantly worsens two to three days after cession of injection of MAb-E25. Moreover, since MAb-E25 is not completely humanized (about 5% mouse sequence remains), neutralizing antibodies may be produced upon a second or subsequent treatments, thus further diminishing the efficacy of this approach (Corne et al., 1997, J. Clin. Inv., 99:879; Milgrom et al., 1999, N. Engl. J. Med., 341:1966). Furthermore, the paratope-specificity of MAb-E25 carries the additional risk of inducing anti-MAb-E25 antibodies, that is to say, anti-idiotypic antibodies (Vogel et al., 2000, J. Mol. Biol., 298:729; Jerne, 1993, Scan. J. Immunol., 38:1) bearing an internal image that mimics the original conformation of the FceRI binding site. Being bivalent, such antibodies can potentially cross-link FceRI and induce mast cell degranulation even in the absence of circulating IgE.
A long-term solution for IgE-mediated allergic diseases is urgently needed. One approach is to actively immunize against IgE. Existing approaches have focussed on using an entire IgE heavy chain domain as the immunogen (Hellman et al., U.S. Pat. No. 5,653,980). Although conceptually attractive, these approaches may lead to severe or even life-threatening IgE-mediated anaphylaxis, since antibodies raised against multiple antigenic epitopes across intact or largely intact IgE domains may cause extensive IgE-mediated mast cells/basophil activation. The contact region between the IgE heavy chain CH2 and CH3 domains and the FceRI receptor spans 5600 Ångstrøm according to the recent crystallographic structure obtained for the complex (Garman et al., 2000, Nature, 406:259). The safety of using MAb-E25 resides in its blocking of the binding to FceRI.
It is believed that conformation-sensitive B-lymphocyte epitopes are poorly represented by their corresponding synthetic, non-conformationally restricted peptides, even when these are coupled to a foreign carrier protein. There is at present no method for identifying and constructing IgE B-lymphocyte vaccines that correspond to constrained epitope such as those at mast cell binding sites. There is thus a great deal of unmet medical need to design other innovative means to reduce levels of IgE production.
In contrast, major histocompatibility class I (MHC class I)-restricted cytotoxic T-lymphocyte (CTL) epitopes are believed to be sequence-dependent. The present invention aims at developing a method of active immunization against IgE, using as immunogen a short stretch of sequence universally present on the IgE heavy chain constant region, independent of any conformation requirement.